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Policy News

Welcome to OncologyPRO, the home of ESMO’s educational and scientific resources, with Guidelines, a comprehensive list of E-Learning modules, Factsheets on biomarkers, slides and webcasts from our educational programme, and more... to support continuing medical education and daily practice!

Lung cancer is one of the leading causes of cancer-related deaths around the world (1, 2). Despite the development of third-generation drugs combined with platinum compounds and different maintenance therapies, the overall survival achieved by cytotoxic agents was no longer than 15 months (3, 4).

Programmed cell death 1 (PD-1) is a negative costimulatory factor expressed on the surface of T-cells. It binds to one of its ligands; PD-L1 or PD-L2 expressed on the surface of neoplastic cells and inhibits a cytotoxic T-cell response. Several antibodies were developed against PD-1 or PD-L1 achieving enthusiastic results in NSCLC (durable response in approximately 20% of the patients) (5-7). Pembrolizumab is a monoclonal humanized IgG4 antibody against the PD-1 that has shown activity in different neoplasms including NSCLC.

KeyNote-001 is a large phase I trial evaluating different doses (2 mg or 10 mg per kilogram every 2 weeks) of pembrolizumab for the treatment of different neoplasms. In 2015 Garon et. al. published the results for NSCLC (8).

Interestingly, patients could be enrolled into the study despite their histology, previous treatment or PD-L1 status. Four hundred ninety five patients were included. The objective response rate was 19.4% and the median duration of response was 12.5 months. The median progression-free survival was 3.7 months and the median overall survival was 12.0 months. Pembrolizumab has shown a manageable toxicity profile with less than 10% of grade 3 or 4 adverse events and pneumonitis incidence of less than 4% with a severity of grade 3 to 5 in half the patients (8).

The most important question is: this treatment is indicated for whom?

In the KeyNote-001 trial, PD-L1 status was assessed by IHC and after a ROC curve it was adopted the cutoff of 50% and it was different from previous trials evaluating anti PD-1 therapies, which have adopted the cutoff of 5%. Nevertheless, the difference among PD-L1 positive and PD-L1 negative neoplasms was the largest ever shown (8).

The response rate was 46.8% among PD-L1 positive patients and 12.3% among PD-L1 negative patients. This difference was significant despite the presence or absence of previous treatment. The median progression-free survival and the median overall survival were better among PD-L1 positive patients (8).

Based on this study, pembrolizumab proved activity for NSCLC despite the presence of previous treatment, however, the main limitation of this study is that it had not any control arm to be compared to pembrolizumab. Moreover, it was not designed for any specific population (previous treated or untreated; PD-L1 positive or PD-L1 negative) and all these conclusions were made based upon subgroup analysis.

Discussion questions

Is PD-L1 a feasible biomarker for anti PD-1 activity?

If the above is true, what is the best cutoff value?

Would it be reasonable to approve pembrolizumab for clinical use after the findings of the present article?

If the above is true, which is the population that would achieve the largest benefit?